Langerhans cell histiocytosis (LCH) is a disease of unknown etiology that affects children and adults. There is very little published data on the biology of Langerhans cells (LHC) that has been correlated with clinical presentation, response to therapy, or occurrence of late effects. This proposal is directed at extending our preliminary data that shows distinctly different profiles of cytokines and growth factors in clinical subgroups of LCH. LHC are members of the dendritic, antigen-presenting cells and can be derived from hematopoietic stem cells or macrophages. LCH is characterized by the proliferation of morphologically normal LHC in a clonal, but non-malignant fashion as well as lymphocytes, macrophages, and eosinophils in varying proportions. The disease may be manifested by involvement of only one organ system such as the skin, lymph nodes, pituitary gland, bone or combinations of these. Such patients constitute a "Low Risk" group and are all eventually cured, but 50% will have at least one relapse. Other patients, especially children less than 2 years of age, may also have infiltrates in the bone marrow, liver, spleen, lungs, or brain and are considered "High Risk" patients. Only half of patients with high-risk findings are cured. A limited number of cytokine genes with apparent increased expression have been identified in LCH lesions by in situ hybridization or immunocytochemistry studies including: tumor necrosis factor alpha (TNF-a), granulocyte, macrophage colony stimulating factor (GM-CSF), lnterleukins-1,-2,-4,-5,-10, and interferon gamma. We have established a method of measuring cytokine and growth factor gene expression in LCH patients using microdissected LHC from LCH biopsies and comparing them to Langerhans cells from skin of normal individuals. Statistically significant increases of cytokines known to inhibit normal immune function were found in the pathologic LHC including IL-10, IL-22 and transforming growth factor beta. We propose: 1) to validate our preliminary findings in a larger number of patients from the international LCH-III study for children and adults in the LCH-Adult study by defining a limited set of genes to use in assessing risk group assignment using quantitative RT-PCR and 2) to test a hypothesis that patients more likely to relapse will have some unique gene expression profile. [unreadable] [unreadable] [unreadable]